The multifaceted roles of mass spectrometric analysis in nucleic acids drug discovery and development

Abstract

The deceptively simple concepts of mass determination and fragment analysis are the basis for the application of mass spectrometry (MS) to a boundless range of analytes, including fundamental components and polymeric forms of nucleic acids (NAs). This platform affords the intrinsic ability to observe first‐hand the effects of NA‐active drugs on the chemical structure, composition, and conformation of their targets, which might affect their ability to interact with cognate NAs, proteins, and other biomolecules present in a natural environment. The possibility of interfacing with high‐performance separation techniques represents a multiplying factor that extends these capabilities to cover complex sample mixtures obtained from organisms that were exposed to NA‐active drugs. This report provides a brief overview of these capabilities in the context of the analysis of the products of NA‐drug activity and NA therapeutics. The selected examples offer proof‐of‐principle of the applicability of this platform to all phases of the journey undertaken by any successful NA drug from laboratory to bedside, and provide the rationale for its rapid expansion outside traditional laboratory settings in support to ever growing manufacturing operations.

Examining DNA Structures with In-droplet Hydrogen/Deuterium Exchange Mass Spectrometry

“…The work presented here suggests that such an approach may expand to include oligonucleotide species. Notably, the development of the robust in-droplet approach is coincident with the proliferation of native MS studies of oligonucleotides [111] and may therefore find increased usage with the growth of this field. That said, the use of in-droplet HDX to distinguish different oligonucleotide structures as well as to elucidate structural information about specific topologies requires further development work.…”

Collision-Induced Unfolding Reveals Disease-Associated Stability Shifts in Mitochondrial Transfer Ribonucleic Acids

“…These challenges demand the development of new technologies capable of studying the higher-order structures (HOSs) of these noncoding RNAs (ncRNAs) both at biologically relevant concentrations and under biologically relevant solution conditions. Recently, ion mobility–mass spectrometry (IM-MS) has emerged as a useful structural biology tool, and its application to nucleic acids continues to show great promise. ,− In short, IM works by separating gas-phase ions by charge and rotationally averaged collision cross sections (CCSs) within milliseconds . In conjunction with MS, ions of the same mass-to-charge ( m / z ) ratio and different CCSs can be readily distinguished.…”

Collision Induced Unfolding Reveals Disease-Associated Stability Shifts in Mitochondrial tRNAs

“…Recently, ion mobility-mass spectrometry (IM-MS) has emerged as a useful structural biology tool, and its application to nucleic acids continues to show great promise. 1,[10][11][12][13] In short, IM works by separating gas-phase ions by charge and rotationally averaged collision cross-sections (CCSs) within miliseconds. 14 In conjunction with MS, ions of the same mass-to-charge (m/z) ratio and different CCSs can be readily distinguished.…”